New understanding of T-cell receptor behaviour presents challenge for immunotherapies
The body’s immune system represents a valiant weapon against disease, and harnessing its power through a technique called immunotherapy is at the forefront of current research to treat cancer and other diseases.
For this reason, this unexpected finding by University of Notre Dame researchers and their collaborators, related to the way two distinctly different peptide antigens react with one T-cell receptor (TCR), presents a significant challenge when building better molecules with which to develop immunotherapies.
The surprising research showing peptide adaptability was presented by Brian Baker, the John A. Zahm, C.S.C., Professor of Structural Biology and chair of the Department of Chemistry and Biochemistry, as principal investigator on the study. He worked with co-authors from Notre Dame as well as Stanford University, Loyola University and the University of Kentucky.
Commenting on the unsettling discovery, lead author Timothy Riley said: “Essentially, we discovered that T-cell receptors can be much more cross-reactive than we previously envisioned, which is somewhat concerning for the entire field.”
Riley is Baker‘s former graduate research assistant and is now co-founder and chief scientific officer of startup Structured Immunity, a company incubated through Notre Dame’s IDEA Center that aims to de-risk early stage immunotherapeutics.
T cells are a subtype of a white blood cell responsible for sensing whether you’re healthy or have an infection, but they often ignore cancer cells as a potential threat. In T-cell immunotherapy, some of the cells are altered so as to contain receptors that allow the T cells to seek and destroy specific, undesirable cells when the receptor reacts with specific peptide antigens – an action required to induce an immune response. While the treatment is effective in some cases, in others it can destroy healthy cells. Researchers therefore seek to predict reactivity and assure the reaction is specific only to the cells they want to target.
Scientists were aware that there were many millions more peptides, or antigen targets, than TCRs. They expected that the receptors recognised and adjusted to many different peptides that have similar properties. In the case of the TCR studied in this particular research – DMF5 – researchers knew it recognised hydrophobic peptide antigens, which are water-insoluble; however, fellow researcher K. Christopher Garcia, the Younger Family Professor and Professor of Structural Biology at Stanford University, noticed that DMF5 also appeared to bind with a different class of peptides – one that was highly charged and easily dissolvable.
Baker‘s lab, having experience in analysing that particular TCR, decided to study further.
“We thought the TCR was ignoring small differences (in the highly charged target) a little bit, and simply found things similar to recognise,” said Baker, who is also affiliated with the Harper Cancer Research Institute. “But that was wrong.
We discovered that this peptide moved and adapted in order for the receptor to bind, in a way that no one had seen before.”
The two different peptide antigens worked equally well at binding with DMF5, stimulating the receptor and inducing an immune response. “It doesn’t really matter how it works, as long as binding occurs,” Riley said.
Though the discovery is notable for increasing the understanding of how to develop immunotherapies, it’s an unexpected challenge to overcome, Bakerexplained. Though the current research was completed on just one TCR and only two peptides were evaluated, he noted, it’s likely that others may function in a similar way.
“What’s significant is that people try to make predictions for developing these models for therapy, and about the kinds of ways you can recognise targets,” he said. “And this is a new, unanticipated complication.”
Researchers have dealt with the knowledge that some TCRs can attack healthy cells as well as the life-threatening ones, and have built that concern into their studies. “But for those people who are trying to take advantage of that biology to develop immunotherapies, you have to be worried about this new issue and build it into whatever design platform…you have,” Baker said.
Armed with this new discovery, however, Riley is up for the challenge. “Now that we have great examples of a T-cell receptor recognising multiple peptide antigens that are structurally different, we can use them to build hypotheses and test predictions,” he said.